The overall goal of the proposed project grant (PPG) is to assemble an interdisciplinary group of talented investigators from different fields to study the biology of ovarian cancer. The general theme of the PPG deals with the growth aspects of ovarian tumor progression. The hypothesis to be addressed is that the onset and progression of ovarian tumors is dependent on aspects of growth regulation (i.e., genetic aberrations, stromal environment, angiogenesis, and local growth facto production) that directly influence tumor categorization, grade and stage. The present application consists of 4 interdisciplinary individual research projects and three core facilities. Project 1. (Michael Skinner) investigates cell-cell interactions and ovarian cancer. The hypothesis tested is that ovarian surface epithelial cells. (OSE) are regulated by mesenchymal (stromal)-epithelial cell interactions mediated by the local production and action of growth stimulators and growth inhibitors. Observations indicate that ovarian tumor growth is dramatically influenced by the stromal environment. The biology of normal and tumorigenic OSE will be examined. Project 2 (Robert Jaffe) investigates angiogenesis in ovarian epithelial carcinoma. The hypothesis tested is that the action of vascular endothelial growth factor (VEGF) is necessary to promote the neovascularization and tumor growth of human ovarian epithelial carcinoma. The extent of angiogenesis and expression of VEGF will also be correlated with tumor progression (i.e., tumor stage and grade). Project 3 (Joe Gray) investigates the role of allelic imbalance in ovarian cancer progression. Using analysis of loss of heterozygosity (LOH), comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH), the chromosomal mapping of common allelic imbalance will be correlated with tumor progression (i.e., tumor stage and grade). Genes will be positionally cloned in regions of common imbalance and, in collaboration with the other projects, genes of interest (e.g., growth factors and receptors) will be mapped and correlated to chromosomal maps. Project 4 (Gordon Mills) investigates a recently purified ovarian cancer ascites factor (OCAF) from ascites fluid of ovarian cancer patients and its role in tumor growth and progression. The hypothesis tested is that OCAF produced by ovarian cancer cells plays a role in tumorigenesis by increasing proliferation of ovarian cancer cells, decreasing sensitivity to chemotherapy, and altering immune responsiveness. These research activities will be supported by the Administrative Core for the coordination and management of the PPG. Thr Molecular Cytometry Core will provide chromosomal mapping (i.e., LOH, CGH and FISH) and technical assistance with FISH of tissue sections. The Tissue/Pathology Core, directed by Bethan Powell, will collect, catalog, and prepare human ovarian cancer surgical specimens and cell-lines for the proposed research. The integrated activities of the four projects and investigators provides a comprehensive examination of the biology of ovarian cancer with emphasis on the growth aspects of tumor progression. Observations are anticipated to provide insight into the future design of more effective therapeutic agents for the prevention, early diagnosis and treatment of ovarian cancer.